Addition of Bevacizumab for Treatment of Platinum-resistant Recurrent Ovarian Cancer

SYNOPSIS: In a trial comparing chemotherapy alone to chemotherapy plus bevacizumab in the treatment of patients with platinum-resistant ovarian cancer, the combination resulted in improved response rates and progression-free survival (PFS) and without a high rate of added toxicity. Whether bevacizumab alone would provide comparable improvements was not assessed but remains an important question for future trials.

Platinum-resistant ovarian cancer, defined as disease relapse within 6 months after platinum-containing therapy, has a notoriously poor prognosis, with a median overall survival (OS) of approximately 12 months.1 At the time of first relapse, approximately 25% of patients have platinum-resistant disease, and eventually nearly all patients with recurrent disease develop platinum resistance. Previous studies have demonstrated that the most active single agents in the platinum-resistant setting are pegylated liposomal doxorubicin (PLD), paclitaxel, and topotecan.2-4 However, combining these chemotherapeutic agents has been shown to increase toxicity without any additional benefit.2,5,6 Because of the poor prognosis for patients with platinum-resistant disease, new treatment strategies are needed. One approach currently being investigated is the use of biologic agents, both as monotherapy and in combination with chemotherapy. Bevacizumab is an inhibitor of vascular endothelial growth factor (VEGF) and has shown activity in platinum-resistant ovarian cancer.7,8

All patients (n = 361) were enrolled between October 2009 and April 2011 and had histologically confirmed epithelial ovarian, fallopian tube, or primary peritoneal cancer that had progressed within 6 months of completing ≥ 4 cycles of initial platinum-based therapy, thereby meeting criteria for platinum-resistant disease. Additional eligibility criteria included: age ≥ 18 years, ECOG performance status ≤ 2, and acceptable liver, renal, and bone marrow function. Patients who received more than two prior treatment regimens and those with refractory disease (progression during previous platinum-containing therapy) were excluded. Additionally, due to the previously reported increased incidence of GI perforation with the use of bevacizumab, patients with a history of bowel obstruction, abdominal fistula, intra-abdominal abscess, rectosigmoid disease involvement by pelvic examination, or bowel involvement on CT scan were also excluded. Additional exclusion criteria included: abdominal surgery within 4 weeks of enrollment, untreated CNS disease, history of thrombotic or hemorrhagic disorders within 6 months of enrollment, uncontrolled hypertension, non-healing wounds or ulcers, and uncontrolled cardiovascular disease.

At the time of enrollment, investigators selected a chemotherapy regimen for each individual patient basis. Regimens included: paclitaxel 80 mg/m2 IV on days 1, 8, 15, and 22 every 4 weeks (n = 115); PLD 40 mg/m2 IV on day 1 every 4 weeks (n = 126); and topotecan 4 mg/m2 IV on days 1, 8, 15 every 4 weeks or 1.25 mg/m2 on days 1-5 every 3 weeks (n = 120). All patients were then randomly assigned to either chemotherapy alone (n = 181) or chemotherapy with bevacizumab 10 mg/kg every 2 weeks (or 15 mg/kg every 3 weeks in patients receiving topotecan every 3 weeks) (n = 179). Treatment was continued until disease progression, toxicity, or patient withdrawal. At the time of disease progression, patients in the chemotherapy alone arm were allowed to cross over to single-agent bevacizumab, and patients receiving both chemotherapy and bevacizumab received standard-of-care treatment (without bevacizumab).

Response was assessed at baseline and every 8 weeks using either CT or MRI, and safety and tolerability were evaluated prior to each cycle. Patients were observed for ≥ 12 months. Median duration of follow-up was 13.9 months in the chemotherapy alone arm and 13.0 months in the chemotherapy-bevacizumab arm.

There was a significant improvement in PFS in patients who received bevacizumab when compared to those who received chemotherapy alone (two-sided unstratified log-rank test: p < 0.001; HR 0.48; 95% CI 0.38 to 0.60). Median PFS was 6.7 months (95% CI 5.7 to 7.9 months) in the chemotherapy plus bevacizumab arm, compared to 3.4 months (95% CI 2.2 to 3.7 months) in the chemotherapy-alone arm. This was seen in all treatment groups, independent of chemotherapy regimen.

Response was evaluated by RECIST in 287 patients. The ORR was 11.8% in the chemotherapy-alone group, compared to 27.3% in the chemotherapy plus bevacizumab group (p = 0.001). There was no statistically significant difference in OS between the two groups (HR 0.85; 95% CI 0.66 to 1.08). Median OS was 13.3 months (95% CI 11.9 to 16.4) in the chemotherapy-alone group versus 16.6 months (95% CI 13.7 to 19.0).

Significant adverse events occurred more frequently in the chemotherapy-bevacizumab group (57% vs. 40.3%). GI perforation occurred in four patients (2.2%) who received bevacizumab and in no patients who received chemotherapy alone. There was an increased incidence of grade ≥ 2 hypertension (20% vs. 7%) and proteinuria (2% vs. 0%) in the chemotherapy-bevacizumab group. Grade ≥ 3 hematologic toxicity was seen equally in both treatment groups.

COMMENTARY

Platinum-resistant ovarian cancer has a poor prognosis, and new treatment modalities are desparately needed. The AURELIA trial is the first randomized phase III study investigating the addition of bevacizumab to standard chemotherapy for patients with platinum-resistant ovarian cancer. The results demonstrate a clear advantage in both progression-free survival and overall response rate with the addition of bevacizumab without a striking increase in toxicity. Overall survival was not influenced, but the frequent cross over to bevacizumab regimens in those who progressed on chemotherapy alone makes this difficult to interpret. Further, there were no unusual or unexpected toxicities with combined bevacizumab-chemotherapy. The study provides a logical "next-step" in the treatment of platinum-resistant ovarian cancer. As we learned from prior from earlier experience with bevacizumab, caution should be raised in patients at risk for perforation including those with significant pre-existing gastrointestinal disease and/or abdominal abscess. Whether bevacizumab-chemotherapy combinations prolong overall survival in this setting will be difficult to prove (i.e., compared to chemotherapy alone), but improved response rate and progression-free survival provide reasonable hope that such would be the case. There is of course, the possibility that bevacizumab alone would provide comparable response rates and progression-free survival as when combined with chemotherapy. This comparison, not included in the AURELIA trial, would seem a logical question for clinical trial.